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PurposeSingle genetic variants in multifactorial disorders typically have small effects, so major increases in disease risk are expected only from the simultaneous exposure to multiple risk genotypes. We investigated the impact of genotype frequencies on the clinical discriminative accuracy for the simultaneous testing of 40 independent susceptibility genetic variants.MethodsIn separate simulation scenarios, we varied the genotype frequency from 1% to 50% and the odds ratio for each genetic variant from 1.1 to 2.0. Population size was 1 million and the population disease risk was 10%. Discriminative accuracy was quantified as the area under the receiver-operating characteristic curve. Using an example of genomic profiling for type 2 diabetes, we evaluated the area under the receiver-operating characteristic curve when the odds ratios and genotype frequencies varied between five postulated genetic variants.ResultsWhen the genotype frequency was 1%, none of the subjects carried more than six of 40 risk genotypes, and when risk genotypes were frequent (> or =30%), all carried at least six. The area under the receiver-operating characteristic curve did not increase above 0.70 when the odds ratios were modest (1.1 or 1.25), but higher genotype frequency increased the area under the receiver-operating characteristic curve from 0.57 to 0.82 and from 0.63 to 0.93 when odds ratios were 1.5 or 2.0. The example of type 2 diabetes showed that the area under the receiver-operating characteristic curve did not change when differences in the odds ratios were ignored.ConclusionsGiven that the effects of susceptibility genes in complex diseases are small, the feasibility of future genomic profiling for predicting common diseases will depend substantially on the frequencies of the risk genotypes.

Original publication




Journal article


Genetics in medicine : official journal of the American College of Medical Genetics

Publication Date





528 - 535


Department of Public Health, Erasmus University Medical Center, Rotterdam, The Netherlands.


Humans, Chronic Disease, Genetic Predisposition to Disease, Risk Assessment, Reproducibility of Results, Gene Expression Profiling, Genetics, Medical, Genomics, Gene Frequency, Genotype, Genome, Human